CD6 is a cell surface protein expressed primarily by T-lymphocytes The increase in CD6 expression that occurs during thymocyte maturation, and following T-lymphocyte activation, indicates an important role for CD6 in these processes. Exploring the function of CD6 is the focus of this proposal. The T cell co-stimulatory molecule CD2 is important in thymocyte selection, and increase in CD6 are induced by stimulation of thymocyte CD2; this raises the possibility that the CD2 induced survival-signal may be mediated by CD6. Although CD6 has not yet been shown to be important during thymic selection, the CD6 ligand, CD166 is expressed on thymic epithelium, and stimulation of CD6 in chronic lymphocytic leukemia B-cells does decrease apoptotic death. Experiments are proposed to study developmental regulation of CD6 expression and phosphorylation by CD2, and to determine if CD2-induced increased in CD6 expression enhance thymocyte survival. CD6 is also increased in activated T lymphocytes, and in autoreactive cloned T lymphocytes. Data showing that anti-CD6 monoclonal antibody UMCD6 inhibits autoreactive responses of such clones in vitro suggests that CD6 may act as a co-stimulatory molecule in vivo during autoimmunity. Survival of autoreactive T lymphocytes has been reported to contribute to autoimmunity in human SLE but a role for CD6 in hum SLE, has not yet been shown. Studies to determine if alterations in the regulation of CD6 and CD6 phosphorylation occur in SLE T cells, and to assess the role of CD6 in co-activation of SLE T cells are proposed in this application. We hypothesize that the function of the T lymphocyte co-stimulatory molecule CD6 is to enhance T-cell survival during thymocyte development, and to transduce activating signals to mature T lymphocyte. Testing the role of CD6 during thymic selection, and n activation in mature T lymphocyte from SLE patients and normal controls, is expected to enhance our understanding of the role of CD6 in human autoimmune disease.